Control of retinoblastoma cell growth by differentiating agents: current work and future directions.

It has become clear over the last few years that malignant transformation for several tumors results from failure of embryonic tissue to properly differentiate and activation of a mechanism which triggers uncontrolled cellular proliferation. Retinoblastoma fits this pattern, in that early inactivation of regulatory genes leads to proliferation of cells that are arrested in a primitive stage of development. Cultured Y-79 human retinoblastoma cells, however, can be induced to differentiate to a more "normal" stage in development through the use of several naturally occurring agents, such as butyrate, cyclic AMP, and retinoic acid. These agents cause reversible growth inhibition (e.g., retinoic acid) or result in cell death (e.g., butyrate). Proteins translated from mRNAs isolated from Y-79 cells are dramatically altered by all the above substances. Thus, alteration in transcriptional activity and changes in macromolecular synthesis can lead to the transition of rapidly growing, non-differentiated retinoblastoma cells to a non-proliferating, more differentiated state. The changes of the mRNA species induced with the various agents we have utilized, supports the hypothesis that differentiation and growth inhibition in Y-79 cells are programmed genetic events which can be controlled at least in vitro. Screening and testing of differentiating agents could be clinically useful for the treatment of retinoblastoma as well as for better understanding the biological control mechanisms involved in tumor growth.